Comparative cardiac safety profiling of ALK inhibitors: an eudravigilance disproportionality analysis

Background

ALK inhibitors have improved outcomes in ALK-rearranged non-small cell lung cancer, resulting in prolonged exposure and increased importance of cardiovascular safety. Clinical trials may under-represent rare or delayed cardiac events, making post-marketing databases such as FAERS and EudraVigilance valuable for real-world signal detection. However, comparative cardiac safety analyses of ALK tyrosine kinase inhibitors in EudraVigilance remain limited.

Purpose

We aimed to explore signals of disproportionate reporting (SDR) of drug–event pairs (DEP) involving ALK inhibitors and cardiac adverse events.

Methods

We screened for signals of disproportionate reporting (SDR) within the MedDRA-defined cardiac disorders system-organ class (SOC), by using cumulative reports from EudraVigilance. Reporting odds ratios (RORs) with no Bayesian shrinkage and corresponding 95% confidence intervals were calculated to enable comparison of reporting frequencies against all other drugs in the database. SDRs were defined as drug–event pairs with a lower bound of the 95% confidence interval of the ROR greater than 1 and a minimum of 5 reports. Inclusion of events in the Important Medical Event (IME) list was pre-specified.

Results

The primary disproportionality analysis revealed distinct drug-specific adverse event patterns. Crizotinib showed robust signals for bradyarrhythmias: bradycardia (ROR 15.49, 13.67–17.56), sinus bradycardia (ROR 26.76, 20.17–35.52), along with pericardial effusions (ROR 7.83, 6.32-9.69). Additional severe adverse events were also reported: cardiopulmonary failure (ROR 10.26, 5.8–18.14), cardiac arrest (ROR 2.30, 1.69–3.13), cardiac failure (ROR 2.03, 1.61–2.55). Ceritinib and brigatinib exhibited similar reporting patterns, predominantly driven by cardiac tamponade (ceritinib: ROR 14.80, 6.14-35.68; brigatinib: ROR 13.24, 5.49-31.91), pericardial effusion (ceritinib: ROR 12.73, 8.63-18.77; brigatinib: ROR 6.07, 3.59-10.28 ), and bradycardia (ceritinib: ROR 4.02, 2.33-6.96; brigatinib: ROR 3.60, 2.08-6.21). Ceritinib was also associated with a high pericarditis signal (ROR 5.46, 3.70–8.04).

Alectinib exhibited similar bradycardia and pericardial toxicity profiles as well as conduction disorders, including atrioventricular block (ROR 3.98, 1.79–8.90). Lorlatinib’s reporting profile was broad and also included severe adverse events, such as cardiopulmonary failure (ROR 15.11, 8.33–27.40), cardiac failure (ROR 1.83, 1.35–2.49).

Conclusion

In this pharmacovigilance analysis, crizotinib was primarily associated with bradyarrhythmias and pericardial effusions, ceritinib and brigatinib with pericardial disease and cardiac tamponade, alectinib with bradycardia and conduction disorders, and lorlatinib with severe cardiac events including cardiac and cardiopulmonary failure. These drug-specific patterns highlight heterogeneous cardiovascular risk and support the need for tailored cardiac monitoring during ALK inhibitor therapy.